Damage to the Brain Serotonergic System Increases the Expression of Liver Cytochrome P450

Abstract

Genes coding for cytochrome P450 are regulated by endogenous hormones such as the growth hormone, corticosteroids, thyroid, and sex hormones. Secretion of these hormones is regulated by the respective hypothalamus-pituitary-secretory organ axes. Since the brain sends its serotonergic projections from the raphe nuclei to the hypothalamus, we have assumed that damage to these nuclei may affect the neuroendocrine regulation of cytochrome P450 expression in the liver. Thereby, 5,7-dihydroxytryptamine (5,7-DHT), a serotonergic neurotoxin, was injected into the dorsal and median raphe nuclei of male Wistar rats. Ten days after the neurotoxin injections, the brain concentrations of neurotransmitters, serum hormone, and cytokine levels, as well as the expression of cytochrome P450 in the liver were measured. Injection of 5,7-DHT decreased serotonin concentration in the brain followed by a significant rise in the levels of the growth hormone, corticosterone, and testosterone, and a drop in triiodothyronine concentration in the serum. No changes in interleukin (IL) levels (IL-2 and IL-6) were observed. Simultaneously, the activity and protein level of liver CYP1A, CYP3A1, and CYP2C11 rose (the activity of CYP2A/2B/2C6/2D was not significantly changed). Similarly, the mRNA levels of CYP1A1, CYP1A2, CYP2C11, and CYP3A1 were elevated. This is the first report demonstrating the effect of intracerebral administration of serotonergic neurotoxin on liver cytochrome P450. The obtained results indicate involvement of the brain serotonergic system in the neuroendocrine regulation of liver cytochrome P450 expression. The physiologic and pharmacological significance of the findings is discussed.

The Effect of Chronic Treatment with Lurasidone on Rat Liver Cytochrome P450 Expression and Activity in the Chronic Mild Stress Model of Depression

“…Finally, it should be mentioned that the observed effects of lurasidone on CYP may be connected with the pharmacological action of the neuroleptic, in particular with its antagonist activity at dopaminergic D 2 , serotonergic 5-HT 2 , and adrenergic a 2 receptors in the brain and/or periphery, which affects the central (Wójcikowski and Daniel, 2009;Sadakierska-Chudy et al, 2013;Rysz et al, 2015;Daniel et al, 2017) and peripheral (Daskalopoulos et al, 2012a;Kot Fig. 6.…”

“…Our earlier studies indicate an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) in the neuroendocrine regulation of cytochrome P450 (CYP) expression in the liver, involving growth hormone, corticosterone, and thyroid hormones (Wójcikowski and Daniel, 2009;Kot and Daniel, 2011;Kot et al, 2012Kot et al, , 2013Kot et al, , 2015Bromek et al, 2013;Sadakierska-Chudy et al, 2013;Rysz et al, 2015Rysz et al, , 2016aKot and Daujat-Chavanieu, 2016;Kot, 2017). The above-mentioned hormones are the main physiologic regulators of CYP genes in the liver (Gibson et al, 2002;Waxman and O'Connor, 2006;Monostory et al, 2009;Dvorak and Pavek, 2010;Brtko and Dvorak, 2011;Monostory and Dvorak, 2011).…”

Serotonin Receptors of 5-HT2 Type in the Hypothalamic Arcuate Nuclei Positively Regulate Liver Cytochrome P450 via Stimulation of the Growth Hormone–Releasing Hormone/Growth Hormone Hormonal Pathway

“…Estimation of the Cytochrome P450 Protein Levels in Liver Microsomes. The levels of CYP2C11, CYP3A1/23, and CYP3A2 in the liver microsomes (10 mg of proteins) of control and 5-HT receptor agonist-treated rats were estimated by western immunoblot analysis, as previously described (Rysz et al, 2015(Rysz et al, , 2016a. Polyclonal rabbit anti-rat CYP2C11, CYP3A1/23, or CYP3A2 antibodies and a secondary antibody (a species-specific horseradish peroxidaseconjugated anti-IgG) were applied (1:2000 dilution of both primary and secondary antibodies).…”

“…The bands' intensity on a nitrocellulose membrane was quantified with a luminescent image analyzer. The data were normalized to protein loading based on the b-actin levels (Rysz et al, 2015(Rysz et al, , 2016a.…”

“…Our earlier studies conducted after damage to or stimulation of the brain serotonergic system by intracerebroventricular administration of the serotonergic neurotoxin 5,7-dihydroxytryptamine or 5-hydroxytryptophan, respectively, showed an important role of this brain system in the physiologic neuroendocrine regulation of cytochrome P450 expression and activity in the liver (Rysz et al, 2015(Rysz et al, , 2016a. Moreover, the results obtained using local intrahypothalamic injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine showed the reverse effect of the serotonergic innervation of the paraventricular nucleus (PVN) and arcuate nucleus (ARC) of the hypothalamus on the regulation of the main male cytochrome P450 enzyme, CYP2C11, in the rat (Rysz et al, 2016b).…”